Elevated intraocular pressure decreases response sensitivity of inner retinal neurons in experimental glaucoma mice

Abstract

Glaucoma is the second leading cause of blindness in the United States and the world, characterized by progressive degeneration of the optic nerve and retinal ganglion cells (RGCs). Glaucoma patients exhibit an early diffuse loss of retinal sensitivity followed by focal loss of RGCs in sectored patterns. Recent evidence has suggested that this early sensitivity loss may be associated with dysfunctions in the inner retina, but detailed cellular and synaptic mechanisms underlying such sensitivity changes are largely unknown. In this study, we use whole-cell voltage-clamp techniques to analyze light responses of individual bipolar cells (BCs), AII amacrine cells (AIIACs), and ON and sustained OFF alpha-ganglion cells (ONαGCs and sOFFαGCs) in dark-adapted mouse retinas with elevated intraocular pressure (IOP). We present evidence showing that elevated IOP suppresses the rod ON BC inputs to AIIACs, resulting in less sensitive AIIACs, which alter AIIAC inputs to ONαGCs via the AIIAC→cone ON BC→ONαGC pathway, resulting in lower ONαGC sensitivity. The altered AIIAC response also reduces sOFFαGC sensitivity via the AIIAC→sOFFαGC chemical synapses. These sensitivity decreases in αGCs and AIIACs were found in mice with elevated IOP for 3-7 wk, a stage when little RGC or optic nerve degeneration was observed. Our finding that elevated IOP alters neuronal function in the inner retina before irreversible structural damage occurs provides useful information for developing new diagnostic tools and treatments for glaucoma in human patients.laucoma is a leading cause of irreversible blindness in the United States and the world (1, 2), and is characterized by optic nerve cupping (thinning of the neuroretinal rim at the optic nerve head) and progressive optic nerve and retinal ganglion cell (RGC) degeneration as well as functional deficit revealed by psychophysical tests (3, 4). Although factors causing the eventual RGC death and blindness remain controversial (1, 5-8), increasing evidence from human patients and animal models has shown that the disease is associated with an early mild diffuse loss of retinal sensitivity or inner retinal response decrease (9-14). Although it is unclear whether these functional changes are a prelude or even causal to RGC death and blindness, elucidating the underlying synaptic and cellular mechanisms for such sensitivity/response decline will nevertheless provide novel insights pertaining to early detection and treatment of human glaucoma.Multiple risk factors are associated with glaucomatous diseases, among which elevated intraocular pressure (IOP) is widely accepted as the most significant for both disease onset and progression (2, 15). Because high IOP (H-IOP) is an important risk factor, many experimental animal models of elevated IOP have been developed in multiple species including monkeys, rats, and mice (16)(17)(18)(19)(20)(21)(22). Most experiments performed in animal models have focused on anatomical and histopathological analyses of RGC death, axon loss, and changes to axonal projections ...

Elevated IOP alters the space–time profiles in the center and surround of both ON and OFF RGCs in mouse

“…To increase the IOP in mice, we used a variation of the microbead occlusion model (10)(11)(12). In all cases the left eye was injected with beads and the right eye was uninjected.…”

“…Our findings support this idea because we also find a reduction in the antagonistic surround strength and size in ON RGCs. The rod ON BC to AII AC synapse (RBC-AIIAC) is an example upstream retinal synapse that is altered with IOP elevation (11). This synapse could contribute to center responses of OFF RGCs (13,20,25) and surround responses of ON RGCs (26).…”

“…Previous reports have shown that high IOP decreases photopic RF center size of RGCs, but its effect on the antagonistic surround and scotopic RFs was not studied (8,9). Multiple circuits underlie the scotopic and photopic RF center and surround and they may be differentially susceptible to IOP (11). We therefore studied how IOP affects different components of RGC spatial processing.…”

“…Blocking this synapse removes all ON pathways, which contribute to OFF RGCs via ON cross-over pathways. Recent work has suggested alteration of specific ON cross-over pathways with IOP elevation (11). Therefore, we wanted to test the hypothesis that some of the IOP-induced functional changes to OFF RGCs are mediated via ON cross-over pathways.…”

Targeting neuronal gap junctions in mouse retina offers neuroprotection in glaucoma

“…The optic nerve has been recognized as the initial site of damage leading to death of RGCs in glaucoma, classifying it as an axogenic disease (1, 2). Emerging evidence, however, indicates that morphological and functional changes in RGCs may occur prior to the optic nerve degeneration (46)(47)(48). Interestingly, the protection afforded to the optic nerve in microbead-injected Cx36 -/-animals is intriguing, in that Cx36 protein is not expressed there, suggestand their CxWT littermates were made under control conditions and then 8 weeks after microbead injection to assess changes in spatial acuity and contrast sensitivity.…”